Search

Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects.

Introduction: Vascular calcification (VC) is a significant risk factor for cardiovascular morbidity and mortality. Based on the mineral deposition site in the arterial wall, VC classifies into intimal and medial calcification. We hypothesize that distinct in vitro mineralization methods promote specific intracellular signalling pathways in vascular smooth muscle cells (SMC), reflecting both VC types. Methods and Results: Human coronary artery SMCs were cultured in osteogenic medium (OM) or high calcium-phosphate medium (CaP) to induce calcification. OM resembles SMCs differentiation in intimal calcification - a key process in atherosclerotic plaque remodeling. CaP is associated with chronic kidney disease - a risk factor for medial calcification. Transcriptomics revealed a distinct gene expression profile of OM and CaP-calcifying SMCs, that share 6.9% and 11.3% of their genes, respectively. The 109 shared dysregulated genes between OM and CaP-calcifying SMCs highlighted enriched pathways related to SMC contraction and metabolism. Real-time extracellular efflux analysis demonstrated a different metabolic profile in OM and CaP-calcifying SMCs. We observed decreased mitochondrial respiration and glycolysis (-57,3% p=0.029) by CaP and increased mitochondrial respiration without altered glycolysis by OM. Subsequent kinome and in silico drug repurposing analysis (Connectivity Map) revealed a distinct role of protein kinase C (PKC). Validation using prostratin, a specific PKC activator, demonstrated differential effects on matrix mineralization that was decreased by OM (-69,3%, p Conclusions: In conclusion, OM and CaP-induced SMC calcification underlies differential mechanisms in vitro. Therefore, research should distinguish between the two aspects of VC and increased knowledge about the underlying pathophysiological mechanisms may open the possibility for preventing intimal and medial calcification.